Our long-standing goal is to understand the role that human papillomaviruses (HPVs) play in the etiology of cancer, and to identify other risk factors that cause only some HPV infected individuals to progress to cancer. Previously we have focused on a group of high-risk genus alpha HPVs and have showed that they have a causal role in anogenital cancers. In addition, we identified immunogenetic factors that influenced the development of cervical cancer. We also identified a number of factors that were known or thought to be associated with immunosuppression, such as smoking and corticosteroid use that were common among the squamous cell anogenital cancers. This prompted us to direct our attention to the possibility that a different set of HPVs, known as genus beta- or EV HPVs, are involved (together with immunosuppression and UV damage) in the etiology of squamous cell cancer of the skin (SCSC). To test this hypothesis Project 1 will establish a nested case control study of SCSC among organ transplant recipients (OTR). We will identify the genus beta HPV types present in SCSC tumor tissue, the types and viral load resident in hair follicles of cases and controls, and HPV antibodies in blood samples drawn prior to transplantation. Associations with HPV markers will be estimated accounting for other SCSC risk factors such as immunosuppressive drugs, sunlight exposure and other characteristics. In a parallel longitudinal study, Project 1 will also examine the natural history of genus beta HPVs in the OTR population. Project 2 will focus on the mechanisms by which the genus beta E6 and E7 proteins contribute to malignancy by studying their ability to bypass UV damage checkpoints, inhibit apoptosis, disrupt p53 function and stimulate proliferation. We hypothesize that infection with genus beta HPVs can lead to increased proliferation of squamous cells, and that the HPV oncoproteins inhibit the normal response to UV-induced DNA damage, i.e. repair or apoptosis, allowing cells with mutations in tumor suppressors or oncogenes to accumulate changes that lead to cancer. Project 3 will focus on identifying genetic risk factors for HPV related cancers. For SCSC in OTRs, polymorphisms in genes in both the innate and adaptive immune response pathways will be interrogated, as well as genes in the UV-induced DNA damage repair pathway. We will also study polymorphisms in genes in the Toll-like receptor pathway in cervical and vulvar cancers, taking advantage of our large population-based cases and controls accrued in prior funding periods. Four cores will support these three projects: Molecular Biology, Pathology, Data Management and Biostatistics, and Administration. If a strong link between specific HPV types and SCSC can be verified in studies such as the ones we propose, this information will have important translational benefit in diagnosis, therapy and prevention. We bring an experienced, highly integrated, multidisciplinary team to address this important problem.